Triple-negative breast cancer (TNBC), a highly aggressive, relapse-prone disease that accounts for one-fourth of all breast cancers, could potentially be treated with immune checkpoint blockade therapy.

Already used to treat other cancers, immune checkpoint blockade therapy relies on connections between PD-L1 and its sister molecule, PD1, found on T-cell surfaces, allowing cancer cells to go undetected by the immune system. Blocking PD-L1 and PD-1 interaction has been the basis for successful immunotherapies already in use in other cancers.

A team of MD Anderson researchers has found that in TNBC, a cell process called glycosylation is required for PD-L1/PD1 molecules to interact and identified exactly how and why glycosylation is so crucial.

“Glycosylation is a process that attaches portions of sugar molecules called moieties to the protein providing it fuel to grow and spread,” said Mien-Chie Hung, Ph.D., chair of Molecular and Cellular Oncology. “Glycosylation of PD-L1 in tumor cells stabilizes PD-L1, but it is largely unknown whether sugar moiety by itself is required for binding to PD-1 to suppress anti-tumor immunity.”

Hung’s research group shed further light in this area through discovery of glycosylated PD-L1 (gPD-L1), and worked with STCube Pharmaceuticals Inc. to develop anti-gPD-L1 antibodies that recognize this glycosylated form of PD-L1, killing tumor cells while not harming healthy ones.

To improve the therapeutic efficacy of anti-gPD-l1 antibody, the team linked a potent small molecule chemotherapy agent, called MMAE, to the anti-gPD-L1, creating a new antibody drug conjugate (ADC), called anti-gPD-L1-MMAE, which resulted in higher therapeutic efficacy in animal models. Hung believes the development of this glycosylated PD-L1 ADC (anti-gPD-L1-MMAE) may represent a new generation of immunotherapy that is more targeted with fewer adverse effects.

“We demonstrated that gPD-L1 is an excellent candidate for ADC as sugar moiety is critical for PD-L1’s detrimental role in TNBC,” said Hung. “Immune checkpoint blockade treatment options remain limited in TNBC, so identifying new immune checkpoint targets to improve upon current therapy is urgently needed.”